2, 4-di-piperidino-5-benzylpyrimidine



2,723,975 2 ,4-DI-PIPERIDINO-5-BENZYLPYRIMIDINE Aaron S. Goldberg, New York, N. Y., assignor to Nepera Chemical Co., Inc., Yonkers, N. Y., a corporation of New York No Drawing. Application April 3, 1952,

t Serial No. 280,392

1 Claim. ,(Cl. 260256.4)

This invention relates to the preparation of certain novel pyrimidine compounds and relates more particularly to the production of novel 2,4-di-substituted-amino-S-benzylpyrimidine compounds.

Compounds containing a pyrimidine nucleus are of wide pharmacological interest since compounds containing the basic pyrimidine structure are known to play an important part in physiological processes. Pyrimidine derivatives of the barbiturate group, for example, constitute an important group of sedative and hypnotic compounds. Other compounds containing the pyrimidine structure are present in the cell nucleus in the form of nucleoproteins. Although the study of the physiologically active pyrimidine compounds has occupied the attentionof many investigators, the usefulness of many compounds which come within the broad class of pyrimidine compounds has by no means been fully determined since it is well known that relatively small changes in compounds have been found to exert widely difierent physiological effects.

It is, therefore, an important object of my invention to provide certain novel 2,4-di-substituted-aminor5-benzylpyrimidine compounds having desirable physiological activity.

Another object of my invention is the provision of certain novel physiologically active 2,4-di-substituted amino-S-benzylpyrimidine compounds which maybe prepared from available or readily synthesized intermediates.

Other objects of this invention will appear from the fol-. lowing detailed description. p

The novel pyrimidine compounds of my invention may be represented by the following formula:

wherein R is a substituted amino gro up Thus, for ex ample, R may be an alkyl-amino group having from 1 to 6 carbon atoms, an aryl-substituted aminogroup, a hydroxyalkyl-substituted amino group wherein the alkyl group may contain from 1 to 4 carbon atoms, the residue of a heterocyclic group which is linked by nitrogen to the pyrimidine nucleus, and an .aralkylrsubstituted amino group. Thus R may be, for example, a methylamino group, a dimethylamino group, a hydroxyethylamino group, an anilino group, a piperidino group, a benzyl amino group, a furfurylamino group, a ,e-phen'ylisopropylamino group, etc. Certain of these compounds have beenfound to have a respiratory analeptic effect on laboratory animals.

The novel compounds of my invention may be obtained by condensing ethyl hydrocinnamate i with ethyl. formate so as to o bt ain the intermediatetc pmpound a-formyl ethyl hydrocinnamate the structure of pyrimidine United States Patentare filtered,

o QCHzilEb-L-O'Uzlis H0 The above compound may then be reacted with urea, for example, in alcoholic solution and in the presence of some hydrogen chloride to yield (a-benzyl-fi-ureido)-ethyl acrylate:

oom-fi- -ooim Example I 57 parts by weight of sodium metal and 2 parts by The ether is separated and the ether evaporated under re The formyl ester is then distilled under a pressure of 1 mm. or less. A yield of 70% of theory of ethyl u-formyl hydrocinnamate isobtained as the product.

parts by weight of the ethyl a-fo rmyl hydrocinna mate thus obtained are added to a mixture has been saturated with hydrogen chloride at mixture thus formed is heated at 50-60. C. for about one hour and, after being allowed to stand at a temperature of about 40 C. for about 12-20 hours, followed by standa ing for about 16 hours at a temperatureof 0--5, C., ethyl. a-benzyl B-ureido acrylate crystallizes out. The crystals washed with 50% aqueous ethyl alcohol and then with a small amount of ether. 1

32 parts by weight of the ethyl a-benzyl fi-ureido acrylate are placed in a suitable reactionvessel and 54 parts by weight of a 2 N aqueous solution of sodium hydroxideare added. Heating is continued at the boiling point for about. 30 minutes. The mixture is acidified with warmed 2N aqueous hydrochloric acid. A precipitate. of S-benzyluracil isobtained on acidification. The mixture is cooled,

r enz t n may that be .j

aqueous and chloroform phases are separated. Thechloroform layeris washed several times with ice water and dried with sodium sulfate. After boiling off the chloroform, 2,4-dichloro 5-benzylpyrimidine is obtained and may be further purified by distillation under vacuum. This compound has a boiling point of 160 C. under 1 mm. pressure.

Example 11 3 parts by weight of 2,4-.dichloro-.S-benzylpyrimidine are heated for 12 hours under .autogenous pressure at a temperature of 100 C. With 18 parts by weight of an ethanol solution saturated with methylamine at 3 C. The reaction product obtained is added to a mixture of 15 parts by weight of water and 30 parts by Weight of ether, agitated, and then separated. The ether phase is washed twice more with 15 parts by weight of water and dried over anhydrous sodium sulfate; The ether is concentrated to small bulk and some petroleum ether added.

The solution is then left at a temperature of 5 C. for 16 hours and the crystals of 2,4-bis-methylamino--benzylpyrimidine which form are then filtered off. A yield of 78% of theory is obtained. This novel compound has a melting pointof 124 C.

Example 111 To 4 parts by weight of 2,4-dichloro-S-benzylpyrimidine are gradually added, with cooling, 20 parts by weight of a 33% by weight solution of dimethylamine in benzene. The reaction mixture is then heated for hours at 100 C. and under autogenous pressure. After agitation with a mixture of 40 parts by weight of Water and parts by weight of ethyl ether, the ether layer is separated and the ether distilled off. Without attempting to crystallize the product, it is then subjected to distillation under a pressure of about 1 mm. of mercury and the distillate crystallizes as it cools. A yield of 96% of theory of 2,4-bis-(dimethylamino)- 5- benzylpyrirnidine is obtained melting at 64 C.

1 E ampl IV A mixture of 3 parts by weight of 2,4-dichloro-5-benzylpyrimidine, 395 parts by weight of absolute ethyl alco-. hol and 6.15 parts by weight of ethanolamine are heated in an autoclave under autogenous pressure at 100 C. for 16 hours. 30 parts by weight of diethyl ether are added to the reaction mixture obtained. The ether layer is extracted three times, about 20 parts by weight of water being employed for each extraction. finally separated and'dried over anhydrous sodium sulfate. The major part of the ether is distilled off and the ether solution cooled to 05 C. and held at that temperature for 16 hours to effect crystallization. The crystals obtained are filtered and then washed with a 50/50 mixture, by weight, of diethyl ether/petroleum ether. A yield of 80% of theory of 2,4-di-B-hydroxyethylamino-5- bcnzylpyrimidine is'obtain'ed, melting at 109 C.

0 Example V 5 parts by weight of 2,4-dichloro-5-benzylpyrirnidineare mixed with about 8 parts by weight of benzene and 11.2 parts by weight of piperidine and the Whole heated in an autoclave at about 100 C. for about 8 hours. The amount of piperidine present should be sufiicient to neutralize all of the hydrogen chloride formed during the reaction and to'provide an excess of 50 mol percent. After heating is completed, 50 parts by weight of diethyl ether are added, the mixture agitated and then washed with successive portions'of water until the water layer obtained Theiether phase is is only slightly alkaline. The ether layer is separated, dried over anhydrous sodium sulfate and then concentrated by evaporating off the ether. Petroleum ether is then added just to the point of crystallization. The product is crystallized out by cooling at 05 C. for 16 hours and the crystals then filtered off. A yield of 70% of theory of 2,4-di-piperidino-S-benzylpyrimidine is obtained, melting at 78 C.

Example Vl To 3 parts by weight of 2,4-dich1oro-S-benzylpyrimidine are added 8.8 parts by weight of anhydrous benzene and then 8.65 parts by weight of cyclohexylamine are added with agitation. An exothermic reaction takes place. When the initial exothermic reaction is complete, the reaction mixture is then heated in an autoclave at 100 C. for 20 hours. The entire reaction mixture is then dissolved in diethyl ether and the ethereal mixture extracted several times with water until the water extract obtained is just slightly alkaline. The ether layer is th n dried over anhydrous sodium sulfate and concentrated by evapora ing off the her. If nece s ry. some p tr um ether may be added to initiate the crystallization of 2,4-di-cyclohexylamin0-5- enzylpyrirnidine. The crystals formed are then filtered oil A yield of 89% of theory of 2,4-di-, cyclohexylamino S-benZyIpyrirnidine is obtained. This novel compound has a melting point of 149 C.

Example VII A mixture of 5 parts by weight of 2,4-dichloro-5-benzylpyrimidine, 4.2 partsby weight of benzene and 11.8 parts "by weight of benzylamine are heated in an autoclave at 100 C. for 14 hours. The mixture is then dissolved in diethyl ether, the ethereal solution Washed with water and the ether layer then separated and dried over anhydrous sodium sulfate. Contact with the anhydrous sodium sulfate should be sutficient only to dry the ethereal layer and extended contact should be avoided to prevent premature crystallization. The product is then recovered from the ether layer by evaporating off the ether. The 2,4-dibenzylamino-S-benzylpyrimidine is obtained in an amount equal to of theory. This novel compound has a melting point of 97 C.

It is to be understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without departing from the spirit of my invention.

Having described my invention,

What I claim is:

2,4-di-piperidino-S-benzylpyrimidine.

References Cited in the file of this patent UNITED STATES PATENTS Hi hin t a1. De 18, 19 1 OTHER REFERENCES 

